3-alkoxy-or 3-aryloxy-2-(diaryl-hydroxy)-methyl-propylamines

ABSTRACT

A 3-alkoxy- or 3-aryloxy-2-(diaryl-hydroxy)-methyl-propylamine of the formula IN WHICH Ar and Ar&#39;&#39;, which may be the same or different, are unsubstituted or substituted aryl groups, R is an aliphatic, aryl or arylaliphatic group, and A is a secondary or tertiary amino group, or an acid addition salt thereof. The compound has coronarodilating properties and central nervous system activity.

United States Patent Mauvernay et al.

[ 51 July 11, 1972 [54] S-ALKOXY-OR 3-ARYLOXY-2-(DIARYL- HYDROXY)-METHYL-PROPYLAMIN ES [72] Inventors: Roland Yves Mauvernay, Riom; Norbert Busch, Loubeyrat; Jacques Simond, Charnalieres; Jacques Moleyre, Mozac, all

of France [73] Assignee: Centre Europeen De Recherches Mauvernay C.E.R.M.

[22] Filed: Jan. 2, 1970 [21] Appl. No.: 447

[30] Foreign Application Priority Data Jan. 3, 1969 Great Britain ..452/69 [52] US. Cl ..260/570 R, 260/247.7 R, 260/247.7 C, 260/294.7, 260/326.5 C, 260/584 C, 424/248,

[51] Int. Cl ..C07c 93/04 [58] Field of Search ..260/5 70 R [56] References Cited UNITED STATES PATENTS 2,881,174 4/1959 Wright ..260/570 X 2,881,216 4/1959 Wright ..260/5 70 OTHER PUBLICATIONS Wright (III), Chemical Abstracts," Vol. 55, pages 13405- 13406 (1961 Primary ExaminerRobert V. Hines AztorneyWaters, Roditi, Schwartz & Nissen in which Ar and Ar, which may be the same or different, are unsubstituted or substituted aryl groups, R is an aliphatic, aryl or arylaliphatic group, and A is a secondary or tertiary amino group, or an acid addition salt thereof. The compound has coronarodilating properties and central nervous system activi- 2 Claims, No Drawings 3-ALKOXY-0R 3-ARYLOXY-2-(DlARYL-HYDROXY)- METHYL-PROPYLAMINES This invention is concerned with certain novel substituted propylamines, with a process for their preparation and with compositions containing them.

We have found that 3-alkoxyor 3-aryloxy-2-(diarylhydroxy) methyl-propylamines of the formula in which Ar and Ar, which may be the same or different, are unsubstituted or substituted aryl groups, R is an aliphatic, aryl or arylaliphatic group, and A is a secondary or tertiary amino group, and their acid addition salts, have remarkable coronarodilating properties and central nervous system activity, and certain of them have bactericidal and anti-virus activity. These compounds are novel and constitute one aspect of the present invention.

It is known that 2-hydroxy-3-alkoxy (and 3-aryloxy)- propylamines have a blocking efi'ect on a-adrenergic receptors and a number of patents refer to these compounds. For example, Belgian Pat. No. 669 40], Dutch Pats. Nos. 64/09883, 65/04268, 66/00177, 66/05692 and 66/08099, French Pat. No. 5190M and US. Pat. No. 3 309 406 describe compounds of the formula:

in which A is a secondary or tertiary amino group and R isan unsubstituted or substituted aryl group, and Belgian Pat. No. 669,789describes compounds of formula II in which R is an aliphatic group.

In Patent applications Ser. No. 749 277 (Aug. 1, 1968) and 842 388 (July 16, 1969) Compounds are described following the formula ('JHz-0R (III) in which A and R have the above-stated meanings and X is -CO-Ar or -NH-COAr, where Ar has the abovestated meaning. While in the compounds of formula I] described in the above-mentioned patent specifications, the p blocking effects are preponderant, such effects are substantially non-existant in the compounds of formula III, and the latter have, on the other hand, remarkable anti-arrythmic and coronaro-dilating effects.

Finally, compounds having coronarodilating properties are described in Belgian Pat. No. 710,852 which describes compounds of the formula:

Ar /0R ;c /CH: can-0H2 C|)H-CH2N\ CH; CH: (IV) and in South African Pat. No. 67/5430 which describes com- 70 in the above formulas R, Ar and Ar have the above-stated meanings.

The compounds of formula I can be prepared from known compounds of formula ll by a two stage process. In the first stage, chlorine is substituted for the hydroxyl group on the carbon atom in the 2- position of the compound of formula II by the action of thionyl chloride, preferably in chloroform. In the second stage, the 3-alkoxy (or 3-aryloxy)-2-chloropropylamine prepared in the first stage is condensed with a bis-aromatic ketone (containing unsubstituted or substituted aryl groups corresponding to the desired values of Ar and Ar) in the presence of sodium in liquid ammonia to give the desired compound. The reactions may be illustrated as follows:

accordance with the work described by El. Anderson in J. Org. Chem., 30, page 3959 (i965).

The following example is given by way of illustration only:

EXAMPLE.

First stage: preparation of N,N-diethyl-(3-isobutoxy-2- chloro)-propylamine. no

ctr-carnelian:

(BH -O-CHz-CHKJHQ:

180 g of thionyl chloride in' ml anhydrous CHCI, were added to a solution of 2! 7 g (l M) of N,N-diethyl-( Z-isobutoxy-2-hydroxy)-propylamine in 400 ml anhydrous CHCI,, with stirring and while the temperature was maintained below 55 After the thionyl chloride had been added, the mixture was heated for a further 4 hours under reflux The solvent and the excess SOC], were evaporated off and the product was poured on to crushed ice and made alkaline with 33 percent aqueous NaOH. The product was extracted with ether, the extract dried over anhydrous Na,SO,, the ether was evaporated off, and the residue distilled in vacuo to give 204 g of the abovenamed product. b.p. (2 rmn Hg)=83; no 1.4390; Yield: 86 percent.

Second stage: preparation of N,N-diethyl-[ 3-is obutoxy-2- (diphenyl-hydroxy )-methyl ]-propylami ne. c1

(i1H-CH; N(C2 :)2 (CHHWCU CHz-OCH2C (CH1):-

C sHs O H 5 g of sodium were rapidly dissolved in 300 ml liquid ammonia. [8.2 g benzophenone (0.l M) dissolved in anhydrous ether were then added. The reaction was allowed to continue for 15 minutes and 22.2 g of the previously-prepared halogen derivative were added to the resulting mauve solution. The color changed slowly to orange-yellow.

After continuing the reaction for 4 hours, 1 1 g of NH Cl was added and the Nl-l formed was allowed to evaporate. The residue was dissolved in water and ether. After decantation, the ethereal phase was extracted with an approx. 4N HC] solution. The aqueous solution was then made alkaline with 40 5 N95 percent NaOH and the organic product was extracted with ether.

After the ether had been evaporated, the residue was dissolved in ethyl acetate and ethanol saturated with HCl was added in sufficient quantity to obtain the hydrochloride.

Analysis of the product obtained gave the following result:

A similar method was used to prepare compounds of formula 1 in which the substituents Ar and Ar are phenyl groups and the substituents R and A have the meanings given in Table 1 hereinafter. Table I also gives the melting point of each compound and the results of analytical tests. Compound No.1 was the product prepared in the preceding example.

TABLE 1 t-iiliiii rii m! Compound M. r'ulvu- 11(1 No. A (T) lam- 1 found 1 CH CzHz. 135 0.111 1.00

CHCH.-- N- Cfi; C24

CH-CH:CHz U cg.

3 CH 150 m5 mo \CII-CH:CH2 i N Cd.

4.. CH; 135 5.34 x

\CH-CH:CH2 N- CH;

5 Cg; CQIS ("1 CHCH2-CH2 z s CHCHz CH;

7 CH,- \N 190 0.7

8 CH; inn 10.01 111.01

9. CH;- Cans 170 10.01 '1.

C2415 to CHJ- 11 CzH5 163 0.3: 11.28

12 CzH5- 4 CH, C 33 162 ".7: 0.511

TABLE 1-Continued Hydrochloride HCl Compound M.P. calcu- IICl No. R A C.) lated found 1s CH CH3 192 10.85 10. 70

1 Fumarate, 130. 2 Fumaric acid, calculated 23.3. 3 Furnan'c acid, found 23.4.

The ,pharmacodynamic properties of the above-mentioned TABLE 3 compoundswere studied by the following methods: C

orocntnc- 2 Com- Dose, nary Frc- Arterial Ultll g kxg. flow, qucncy, pressure. gauge, I'U o. t r r l. [)0] Cell I)(l'( Gill. [)Llullll {)(Rllil [)UCl ill H t g T 50 128.2 123.8 18.2 ll26.25 Theacute toxlcttyrn mice was determined by the method of g T 13 l -g 1 -f 1 L B. Behrens and C. Karber (Arch.f.Exp.Path. Pharm., 177, 5 1 211 l iii-g i i 3790935)). 2 t an ta s 1251 has 1 115.7 the results obtained for the compounds set out in Table [are 5 T 3 '1; i 12 l I d showninTableZbelow. 5 T 33 T 17 i 14 T 18 5 t 56 1 14 t 6 T 7 2 ers t. u T 1r 27 TABLE2 5 1 112 T 8 T 35 i it? i 1-13 turns Compound LD50(mg/kg) Compound LD 50 (mg/kg) I J4 L" l m; No-pems Pems 5 t 58 l z s i l) l I 10!; start 1- 132355 5 1 56 i 3 i 5 l 7 g 27 l l000 10 450 2 000 11 600 35 Unmodified. Unmcasumblo. 3 300() 12 385 4 3000 l3 600 2 106106) Y; Ill. ACTION ON THE CENTRAL NERVOUS SYSTEM 7 600 16 A. Stud of thes ontaneous mobili of the mouse 0 en- 8 200 17 600 LD50 900 fiel'dtesoy P W p ll. CARDlO-VASCULAR ACTION After being anaesthetized with chloralose (an 8 percent solution, 10 ml/kg l.V.), the test animal was tracheotomized and made to breath artificially; the chest was opened on the right after resection of the fifth rib. The pericardium was opened and a bridge strain gauge was sewn on the right ventricle. A hole was made in the right auricle, through which a catheter of the largest possible diameter was inserted into the coronary sinus and a transfixion point was placed in position and tightened around the auricular opening of the coronary sinus, in order to collect all the blood which flowed out. The animal was treated with heparin (830 units/kg).

The venous blood flowed into a rotameter and then over an oxygen electrode (a Beckman macro-electrode). The blood was returned to circulation through a catheter which was inserted into an external jugular and pushed very close to the auricular opening of the anterior vena cava.

The arterial pressure was recorded at a carotid artery. Cardiographic electrodes were implanted in a D, arrangement. The following parameters were recorded on a Beckman dynograph the coronary venous flow,

the partial pressure of oxygen in the coronary venous blood,

the carotid arterial pressure,

a D electrocardiogram for measuring the cardiac frequenc and the strength of the myocardium contractions measured by the ventricular gauge.

The results obtained with the compounds identified in Table l are given in Table 3 below, which shows their remarkable acn'vity.

Procedure.

Male animals having a weight of from 17 to 20g were divided into groups of 10 and received, by oesophageal intubation, after fasting for 2 hours, the compound to be tested (treated animals) or an equivalent quantity of the solvent used (control animals).

One hour after the administration of the compound or the solvent, the animals were placed in groups of two in a circular passage. The latter was swept by six beams of infra-red light. The beams were radially directed, equidistant and each centered on a photo-electric cell.

Each breaking of a beam caused by the passage of an animal was recorded on a counter. The number of breaks, and therefore of movements of the two animals, was taken at the end of 10 minutes. The resulm obtained with the treated animals were expressed in the form of a percentage increase or reduction with respect to those obtained with the controls.

B. Study on protection against a lethal dose of cardiazol Groups of 10 male mice having an average weight of 23 g received orally the compound to be tested (or, in the case of the controls, the equivalent weight of the physiological solvent used) and thirty minutes afterwards, mg/kg of cardiazol (pentetrazol), a convulsant of predominantly cortical action, were administered intrap'eritoneally to the animals.

The number of animals which did not die during the 60 minutes following the injection of cardiazol were noted.

C. Protective action in mice with respect to supramaximal electric shock and a lethal dose of strychnine.

Procedure.

One hour after receiving the compound to be tested orally, groups of i0 male mice weighing from 22t'o 26 g, were subjec wd to a supramaximal electric shock (square current of constant intensity: 50 milliarnps, 40 cycles/second, 10 milliseconds over a period of 0.2 seconds by means of corneal TABLE 4 Action against supra- Action against maximal electric Action on lethal dose of shock mobility, percardiazol, percent (dose: cent protection Dose Percent Compound 80 rug kg. (dose: 50 mg. (mg/kg.) protec- No. per 05) kg. per s) per tion 2 Test not effected 3 L115 0 Test not effected 4 1 l4 0 1,000 0 5 i 0 1,000 20 6 1 12 (J 250 0 T T 80 45 50 50 8 i H3 100 20 40 J 22 55 5 B0 1 T 7 0 100 90 11. S2 0 I00 0 12. i 60 50 25 40 13. T 61 0 300 50 14 56 50 50 T0 15 53 0 250 (J 16 54 U 300 0 1T 64 0 300 0 l5 .t 100 54 1 Test not effected. 5 ED ge=6 mgfkg. per 05. Y ED yi=17 mg/kg. per 05.

IV. BACTERIOSTATIC ACTIVITY Procedure.

The study was carried out by the dilution method in liquid medium (variable volume dilution method). The medium used was the standard broth for the study of antibiotics (Institut Pasteur of Paris, Cassagne 1961). Dilutions of the compounds to be tested wee added to the medium to obtain final concentrations ranging stepwise from 10 to 500 uglml. These dilutions were obtained in distilled water from a mother solution in ethylene glycol.

The test bacteria used were a strain of staphylococcus aureus Oxford A268 and of Escherichia coli 548 IP. The tubes were inoculated with dilutions ofa 24 hour culture of the bacteria so as to obtain a final dilution of the inoxulum of 10- for the staphylococcus and of 10" for the Escherichia coli. The tubes were placed in an oven maintained at 37 C and examined after 24 hours and 48 hours. The minimum concentration which totally inhibited the bacteria studied was noted (the minimum inhibiting concentration, M.l.C., is expressed in rig/ml). Results:

Compoun Staphylococcus Coli bacillus No. l 50-l00 #g/ml 500 ug/ml 3 30-l00 uglml 500 ug/ml The compounds of formula I therefore appear to be suitable for the treatment of the following indications:

myocardic anoxia,

coronary insufficiency, angina,

myocardial infarctus, and

cardiac insufiiciency linked with coronary circulation difficulties. They also have anti-convulsant and central nervous system stimulating activity.

For use in human or veterinary medicine, the compounds of formula I may be administered orally, rectally or parenterally. For oral administration, they may be formulated, for example, as compressed tablets, pastilles, capsules or granules; dosage units for oral administration preferably contain 0.250 g of the active compound.

For rectal administration, they may be formulated as suppositories or rectal capsules, preferably containing 0.50 g of the active compound. A dose of 0.050 g is preferably used with parenteral administration. In each case, the active compounds are associated with an inert, physiologically acceptable excipient or under appropriate to the intended mode of administration.

What we claim is:

1. A compound of the formula wherein R is lower alkyl or phenyl and A is a dialkylamine, and acid addition salts thereof.

2. A compound as claimed in claim I wherein R is methyl and A is dimethylamine. 

2. A compound as claimed in claim 1 wherein R is methyl and A is dimethylamine. 